Immunotherapeutic strategies capable of targeting HIV- infected T cells may improve immune control of AIDS. In particular, vaccine stimulation of HIV-specific T cell responses during T cell recovery and reduced viral burden induced by anti-retroviral therapy could induce containment of residual virus. Particle-mediated DNA (PMD) immunization to the skin administered in combination with the anti-retroviral drug, PMPA, during acute SIV infection in monkeys induced immune containment of viremia after discontinuing drug therapy. Interestingly, PMD immunization was highly effective in monkeys that responded well to PMPA, but less effective in animals that showed little or no response to the drug. Increasing DNA vaccine potency may improve immunotherapy in both antiviral drug responders and non-responders. Preliminary results show that co-administration of DNA vaccines with an adjuvant vector encoding the E. Coli heat-labile enterotoxin, LT, enhances T cell responses in mice and monkeys. These results indicate that LT may improve immmunotherapuetic efficacy of DNA vaccines via enhancement of virus-specific T cell responses. The goal of this project is to test an LT-adjuvanted DNA vaccine in the SIV model for AIDS for the ability to improve DNA vaccine immunotherapy in anti-retroviral responders and non-responders via enhanced induction of virus-specific T cell responses. To closely mimic HIV infection in humans, the LT-adjuvanted DNA vaccine will be tested in monkeys chronically infected with a primary isolate of SIV and in combination with HAART. The design of the SIV DNA vaccine closely mimics a clinical HIV-1 DNA vaccine vector that is on a clinical track for human evaluation via the joint clinical development efforts of PowderJect Vaccines and GlaxoSmithKline. These studies are designed to demonstrate feasibility of the approach and support rational design of human clinical trials that aim to test PMD vaccines for immunotherapy in HIV-infected patients The specific aims are to: 1) Test a clinically relevant unadjuvanted DNA vaccine in combination with HAART for therapy of chronic SIV infection in HAART anti-retroviral responders and nonresponders. 2) Test an LT-adjuvanted DNA vaccine in combination with HAART for therapy of chronic SIV infection in anti-retroviral responders. 3) Characterize mucosal immune responses induced following therapeutic immunization with adjuvanted and unadjuvanted DNA vaccines.